Closing element for closing a container for samples for analysis

ABSTRACT

The application relates to a closing element for closing a container for samples for analysis, particularly biological samples. The application also relates to an assembly of a container and a closing element connected to the container. The application also relates to a device and method for analyzing samples. The closure comprises a vent channel (6) with a bacterial filter (7), a penetrable element (5) and the vent channel is configured to be connected with an analyzer and can be opened and closed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the United States national phase of InternationalApplication No. PCT/NL2013/050325 filed May 1, 2013, and claims priorityto The Netherlands Patent Application No. 2008737 filed May 1, 2012, thedisclosures of which are hereby incorporated in their entirety byreference.

BACKGROUND OF THE INVENTION Field of the Invention

The invention relates to a closing element for closing a container forsamples, particularly biological samples. The invention also relates toan assembly of a container and a closing element connected to thecontainer. The invention also relates to a device for analysing samples,particularly biological samples, by making use of an assembly accordingto the invention. In addition, the invention relates to a method foranalysing samples, particularly biological samples, by making use of anassembly according to the invention.

Description of Related Art

The use of electronic noses makes it possible to determine a compositionof gases from which one or more diseases such as asthma, tuberculosis,diabetes, Parkinson's, pneumonia and cancer can be diagnosed. Components(including bacteria) in samples, particularly biological samples, can inaddition be identified and/or characterized on the basis of the gasgenerating metabolism they display. A biological sample, such as forinstance a blood, saliva or urine sample, is for this purpose taken froma person, wherein metabolic gas generation will occur in the sample as aresult of microbiological activity in the sample, wherein the molecularcomposition of the formed metabolic gases can be analysed with anelectronic nose. The sample is injected here by means of a hollowinjection needle into a closed sample bottle. A culture medium ispreferably present in this sample bottle. The sample bottle is closedhere by means of a cap provided with a septum (rubber disc) throughwhich the injection needle can be placed. Following injection of thesample into the closed sample bottle, a hollow analysis needle will beintroduced via the septum into the sample bottle, wherein a spaceenclosed by the analysis needle is connected to an electronic nose. As aresult of diffusion and possible convection flow, metabolic gas formedin the sample bottle will displace via the analysis needle to theelectronic nose, where the composition of the metabolic gas can be atleast partially determined. Although this virtually new techniqueprovides considerable advantages and options, this technique also hasvarious drawbacks. A significant drawback of the known method is thatapplication of an analysis needle creates the risk of a laboratorytechnician being injured and possibly infected, which is especiallyundesirable. In addition, it is recommended that the sample remain asintact as possible after the measurements with the electronic nose, sothat optional further analysis with other test equipment is impeded aslittle as possible. An object of the invention is to provide an improvedcomponent and an improved method enabling relatively safe analysis ofbiological samples.

SUMMARY OF THE INVENTION

The invention provides for this purpose an improved closing element forclosing a container for samples, particularly biological samples,comprising: at least one penetrable element enabling injection of asample via the closing element into a container connected to the closingelement, and at least one ventilating channel provided with at least onebacterial filter, which bacterial filter is substantially impermeable tobacteria and is at least permeable to at least one metabolic gas formedin the sample, which ventilating channel is configured for connection toa device for analysing metabolic gas, wherein the at least oneventilating channel is closed in substantially unloaded state by anotherpart of the closing element, in particular a closing body of the closingelement, and wherein opening of the ventilating channel takes place byloading at least a part of the closing element. A significant advantageof the closing element according to the invention is that the closingelement comprises one or ventilating channels via which (metabolic) gascan displace freely, generally as a result of diffusion and possibleconvection flow, from the container provided with the biological sampleto a space or area outside the container, where the (metabolic) gas canbe collected and can be analysed. When a plurality of ventilatingchannels are applied, it is possible to envisage the ventilatingchannels debouching into one central (shared) bacterial filter. It ishowever also possible to envisage each ventilating channel debouchinginto and/or being provided with its own filter, optionally with its owncharacteristic filtering action. An additionally applied pressuredifference can optionally provide for a more effective displacement ofgases. It is thus no longer necessary to have a relatively unhygienichollow analysis needle pierce the closing element, which is particularlyadvantageous from the viewpoint of hygiene and safety. Possiblecross-contamination between different sample analyses can also beprevented in this way. Applying one or more gas-permeable bacterialfilters, such as a HEPA filter (High Efficiency Particulate Air filter)or a membrane, is advantageous in keeping bacteria present in thebiological sample as far as possible in the container so as to preventcontact as far as possible between the bacteria and analysis equipmentand/or bystanders The bacterial filter will usually be configured forsubstantially free passage of gases from the container to thesurrounding area and vice versa. The at least one ventilating channelwill be positioned at a distance relative to an injection location ofthe closing element. The at least one ventilating channel willpreferably be positioned here at a distance relative to the at least onepenetrable element. Creating a mutual distance between the at least oneventilating channel and the injection location can ensure that aninjection needle pierces only the penetrable element during injection ofa biological sample, and so not by mistake also the ventilating channeland the bacterial filter incorporated therein or co-acting therewith,which would result in undesired leakages via which bacteria could escapefrom the container. This penetration with an injection needle will takeplace if it is desired to suction up and use part of the sample for afurther analysis following the measurement with the electronic nose. Theinjection location will generally be positioned substantially centrally,on or close to a longitudinal axis of the closing element, whereby it isadvantageous for the penetrable element to be also positionedsubstantially centrally. The at least one ventilating channel ispreferably positioned at a distance from the centre of the closingelement, so eccentrically, whereby unintentional penetration of theventilating channel and/or the bacterial filter can be prevented as faras possible. It is also possible to envisage extracting sample receivedin the container, generally with use of a hollow needle, from thecontainer via the penetrable element. It is possible to envisage,although this is generally not recommended, injecting the sample intothe container and only then providing the container with the closingelement according to the invention. If the container is filled in thismanner it would be possible to envisage no longer providing the closingelement with a penetrable element.

The at least one ventilating channel of the closing element issubstantially closed (blocked) when the closing element is at rest andthe ventilating channel will be opened as soon as an external pressure(overpressure or underpressure) is exerted on at least a part of theclosing element. This external (and/or internal) pressure can forinstance be realized by co-action of the closing element with a devicefor analysing biological samples according to the invention. Theadvantage of blocking the at least one ventilating channel in unloadedstate of (an upper side of) the closing element is that metabolic gasesremain conserved as far as possible in the container until the at leastone ventilating channel is opened by loading of the closing element.Such a blocking can for instance be realized by applying apressure-controlled seal or valve forming part of the closing element.An end surface of the at least one ventilating channel preferablyconnects in substantially unloaded state to substantially another partof the closing element, in particular the closing body, wherein theventilating channel and the other part of the closing element, inparticular the closing body, are displaced relative to each other whenat least a part of the closing element is loaded such that opening ofthe ventilating channel takes place. In this embodiment the closing bodydoes in fact function as a pressure-controlled valve.

The closing element is preferably configured such that the ventilatingchannel will open after a predefined external pressure has developed,optionally in combination at at least one predefined location on theclosing element. Unintentional opening of the ventilating channel can inthis way be prevented. It is also possible to envisage the closingelement being configured such that the ventilating channel will openonce a predefined internal gas pressure has developed, this generallybeing realized by the development of metabolic gas in the container. Ahigh overpressure in the container can in this way be prevented, thisgenerally being advantageous from a safety viewpoint. In this embodimentthe closing element, and particularly the closing body, thus functionsas a type of pressure relief valve.

In an advantageous embodiment an upper end surface of the at least oneventilating channel is closed in substantially unloaded state by theother part of the closing element, in particular the closing body. Suchan orientation implies that the ventilating channel is positioned underthe closing body and preferably enclosed by the closing body, wherebythe ventilating channel can be screened relatively well from thesurrounding area, whereby contamination of the ventilating channel withmolecules from the surrounding area can be prevented as well ascontamination of the surrounding area with molecules from theventilating channel. This generally enhances the accuracy, and therebythe quality of the analysis of metabolic gases to be performed.

The closing body usually takes a cap-like form. A closing body comprisesfor this purpose a generally cylindrical peripheral wall, optionallyprovided with for instance screw thread and/or bayonet closure, and anupper wall. The closing body, particularly an upper wall thereof, ispreferably provided with at least one analysis opening configured forconnection to a device for analysing metabolic gas. The analysis openingwill generally also be used to at least partially expose the penetrableelement, whereby the sample can be injected quickly and efficiently.Metabolic gas developed in the sample will accumulate at least partiallyas headspace (gas phase/vapour phase) above the sample. These metabolicgases for analysis can be discharged via the ventilating channel andsubsequently via the analysis opening in the direction of the analysisdevice. It is advantageous here that the analysis opening of the closingbody and the ventilating channel do not lie in line. This preferablyimplies not only that the respective axes of the ventilating channel andthe analysis opening do not coincide (lie out of line), but also thatthe two openings do not overlap each other, whereby the metabolic gasescan only leave the closing element via a non-linear path. Such anorientation generally facilitates the ability to selectively block andopen the ventilating channel.

The bacterial filter is preferably incorporated into the ventilatingchannel. The bacterial filter is preferably closed all around here by atleast one channel wall of the ventilating channel. The bacterial filtercan in this way be screened and held in position relatively well, whichgenerally enhances the filtering action of the closing element as such.

In a preferred embodiment of the closing element according to theinvention the penetrable element is formed by a septum connected toanother part of the closing element. The end surfaces of the septum willbe at least partially clear here, whereby the septum forms a part of theupper surface and a part of the lower surface of the closing element.The septum is manufactured from an elastic material which can be piercedrelatively easily with an injection needle. After removal of theinjection needle from the septum, the septum will close again insubstantially medium-tight manner. A suitable type of material for themanufacture of the septum is an elastomer, in particular rubber. Theseptum can here form a separate element connected by means of welding,glueing or clamping to another part of the closing element. It ishowever also possible to envisage the septum forming an integral part ofthe closing element which can be manufactured substantially wholly froman elastic material. It is possible to envisage the penetrable elementbeing formed by a weakened portion of the closing element. A weakenedportion is particularly understood to mean a part with a small materialthickness, this facilitating piercing by an injection needle. It is alsopossible to envisage the weakened portion having the same materialthickness as adjacent parts, but wherein the weakened portion isweakened by for instance micro-perforations arranged by means of alaser. In this embodiment the weakened portion can also form an integralpart of the closing element as such. The weakened portion is howevermore preferably manufactured here from an elastic material, inparticular an elastomer, whereby the weakened portion could also bedeemed as septum.

As stated above, the bacterial filter can be formed by a HEPA filter. Inan alternative preferred embodiment the bacterial filter is formed by amembrane. The membrane will generally be easy to position in or on aventilating channel. The membrane can here optionally take a somewhatflexible form, which can facilitate attachment of the membrane. Themembrane can optionally be of selective nature here, and can forinstance be configured to block—in addition to bacteria and/orproteins—one or more specific gaseous molecules, such as for instancecarbon dioxide, wherein other gaseous molecules would be able to passthrough the membrane. This separation can take place on the basis of forinstance molecule size and/or polarity. It is possible in this way toallow only the molecules characteristic of a clinical picture to passthrough the membrane, which can considerably enhance the final sampleanalysis. Each bacterial filter will generally be provided with pores(microchannels). In order to have as many bacteria as possible blockedby the bacterial filter, it is advantageous for the bacterial filter tocomprise pores with a maximum diameter of 45 micron. The diameter of theat least one ventilating channel preferably lies between 0.5 and 50millimeters, more preferably between 0.5 and 10 millimeters, inparticular between 1 and 5 millimeters. The bacterial filter can bepositioned here at least partially in the ventilating channel. It isalso possible to envisage the bacterial filter closing an outer end ofthe ventilating channel. The bacterial filter and the ventilatingchannel generally connect substantially medium-tightly to each other inorder to preclude the possibility of (metabolic) gas or bacteria passingthrough the closing element while bypassing the bacterial filter. It isotherwise possible to envisage the closing element comprising aplurality of ventilating channels, wherein each ventilating channel isprovided with at least one bacterial filter, which can for instance beadvantageous for purposes of analysis. Applying a plurality ofventilating channels makes it possible for instance to perform severalsimilar or different analyses separately of each other for a singlebiological sample.

The closing element is preferably configured to at least partiallyenclose (engage round) the container. The closing element will in thisway function as cap for the container. It is however also possible toenvisage giving the closing element a form such that it is configured tobe at least partially received in the container. The closing elementwill in this way function mainly as a stopper. It is also possible toenvisage giving the closing element a form such that the closing elementis configured to grip round the container and to protrude into thecontainer (neck).

The closing element can here be clamped in or round the container.However, in order to realize a more secure coupling of the closingelement relative to the container, it is advantageous for the closingelement to comprise coupling means for coupling the closing element tothe container. The coupling means are generally configured here forco-action with counter-coupling means forming part of the container. Thecoupling means are preferably formed by screw thread for realizing ascrew thread connection. It is also possible to envisage the couplingmeans being configured to realize a bayonet closure or snap connection.

In an embodiment of the closing element according to the invention theclosing or opening of the ventilating channel is not necessarilyselective. Such a closing element for closing a container for samplesfor analysis, particularly biological samples, comprises: at least onepenetrable element for injecting a sample via the closing element into acontainer connected to the closing element, and at least one ventilatingchannel provided with at least one bacterial filter, which bacterialfilter is substantially impermeable to bacteria and at least permeableto at least one metabolic gas formed in the biological sample, whichventilating channel is configured for connection to a device foranalysing metabolic gas. The above stated embodiment is also describedin the Netherlands priority application NL2008737, the content of whichforms part of the description of this patent specification by way ofreference.

The invention also relates to an assembly of a container for a sample,particularly a biological sample, and a closing element according to theinvention connected to the container. The container will be formed hereby a flask or bottle. The container will usually comprise a containerbody and a container neck connected to the container body, wherein theclosing element is generally connected to the container neck. Thecontainer is usually manufactured from a light-transmitting materialsuch as plastic or glass, so that the content of the container isvisible at a glance. It is moreover possible in this way to opticallymeasure the pH of the biological sample in relatively simple manner. Theclosing element is generally manufactured substantially from plastic.The biological sample can be a human sample, an animal sample or avegetable sample. Non-biological samples on which bacterial growth takesplace could optionally also be arranged in the assembly according to theinvention for analysis purposes.

The invention further relates to an (interrelated) device for analysingbiological samples by making use of at least one assembly according tothe invention, comprising: at least one support structure for supportingat least one assembly of a container provided with a biological sampleand a closing element connected to the container, at least one topstructure connected or connectable to the support structure, wherein thetop structure comprises at least one analysis compartment, whichanalysis compartment is configured for substantially medium-tightconnection to at least one ventilating channel of the closing element ofthe assembly, and wherein the analysis compartment comprises at leastone chemical trace detector for detecting at least one metabolic gasformed in the biological sample. The top structure, in particular theanalysis compartment, is preferably configured to load (exert pressureon) the closing element of the assembly such that the ventilatingchannel will be opened as a result and displacement of metabolic gas inthe direction of the analysis compartment can take place. Advantages ofthis selective opening of the ventilating channel have already beendiscussed in the foregoing. Having the analysis channel connect insubstantially medium-tight manner to an outer side of the closingelement so that the analysis compartment is in communicative connectionwith at least one ventilating channel enables metabolic gas, dischargedas a result of diffusion and/or convection flow, to be guided via theventilating channel to the chemical trace detector for purposes ofanalysis. Neither the closing element nor the container need bepenetrated here by the device. In order to realize the substantiallymedium-tight closure it is advantageous for the top structure to engageunder bias on the at least one closing element, preferably via at leastone sealing element. The chemical trace detector in fact forms anelectronic nose for detecting characteristic metabolic gases orcombinations of gases which are usually formed in small quantities(traces) in the biological sample. These metabolic gases consistgenerally of volatile organic compounds (voc) The electronic nose can beof diverse nature, construction and operation. Use is however preferablymade of a chemical trace detector configured to allow reaction(oxidizing or reduction) of at least one or more metabolic compounds,this resulting in a detectable, characteristic, temperature-dependentresistance change in the trace detector. The chemical trace detectorpreferably comprises for this purpose at least one semi-conductingsensor, at least one heating element for heating the semi-conductingsensor, at least one processor for controlling the heating element and adetection circuit for detecting the change in resistance of thesemi-conducting sensor which is at least partially determined by thepresence of at least one chemical trace which reacts in the presence ofthe semi-conducting sensor. Heating the semi-conducting sensor willinitiate redox reactions on or close to the sensor with one or moremetabolic products as reactant, which results in a detectable,characteristic, usually temperature-dependent change in resistance ofthe semi-conducting sensor. In order to stimulate the occurrence of—adetermined type of—redox reaction(s) a catalyst, usually manufacturedfrom platinum or palladium, can optionally be arranged on or in thesemi-conducting sensor. The semi-conducting sensor is preferablymanufactured here from a semi-conductor, more preferably a metal oxide(MOS), in particular tin oxide, zinc oxide, iron oxide, tungsten oxideand/or cesium oxide. The material of the sensor is preferablymanufactured from a sintered granular material, more preferably withsemi-conductor properties. Applying a sintered granular materialgenerally increases the effective sensor surface area and creates grainboundary transitions, this enhancing the sensitivity of the sensor. Athigher temperatures redox reactions take place with oxygen which isadsorbed to the sensor surface and which, depending on the temperature,can be present in different forms. In some cases it is also possible fora chemical trace, without the adsorbed oxygen, to itself undergo a redoxreaction on the sensor surface, in particular the metal oxide surface.Both oxidation and reduction are therefore possible on the sensorsurface. Measurable redox reactions take place substantially always onthe surface (crystal lattice) and substantially not in the vicinitythereof. Chemical reactions with reactive particles, such as forinstance desorbed radicals, could possibly take place above the sensorsurface, although if no electrons are exchanged with a crystal latticeof the (semi-)conducting sensor it will generally not then be possibleto measure a change in resistance of the sensor. Chemical traces willthus usually first adsorb to the sensor surface, after which thechemical traces will react, followed by desorption of the reactionproducts. The detected temperature-dependent change in resistance ishere the result of all chemical reactions taking place on the sensorsurface at a determined temperature. The presence of one or morecharacteristic chemical traces or groups of chemical traces in thesample results in a (known) characteristic contribution toward theresistance change at a pre-known temperature. By measuring theresistance change at different temperatures a temperature-dependentpattern of resistance change is obtained which can be compared to one ormore stored reference patterns, on the basis of which it is possible todetermine relatively precisely which characteristic chemical traces arepresent in the sample. The sensor as such can take a substantiallyplate-like form, which generally facilitates heating of the sensor bymeans of the heating element. The heating element is configured to heatthe semi-conducting sensor to a typical temperature of between 200° C.and 600° C. It is important here to be able to precisely regulate thetemperature of the heating element since the temperature usuallydetermines the type of chemical compound (chemical trace) which reactson the sensor surface, and is thereby related to a measuredcharacteristic change in resistance of the sensor. The heating elementwill generally be of electrical nature and comprise one or moreelectrical resistor tracks or a Peltier element. The processor ispreferably configured here to regulate the specific resistance, andthereby the temperature, of the one or more resistor tracks. A furtheradvantage of the applied chemical trace detector is that the detector isrelatively insensitive to fluctuations in temperature and air humidity,this enhancing the applicability of the chemical trace detector. Theheating element is configured to heat the semi-conducting sensor to atypical temperature of between 200° C. and 600° C. A suitable sensor isdescribed in WO 2007/061294, the content of which forms part of thispatent specification by way of reference. The advantage of this specifictype of trace detector (sensor) for the analysis is that it can take arelatively compact form and that sample analyses can be performed inrelatively accurate and reproducible manner. The analysis compartmentwill usually take a channel-like form.

In a preferred embodiment the processor of the chemical trace detectoris configured to determine at least a part of the composition of the gasmixture coming from the tested sample on the basis of the resistancechange detected by the detection circuit. Comparing the detectedresistance profile (resistance pattern) to a resistance profile, orinformation related thereto, prestored on a storage medium, generally ina database, makes it possible to determine on the basis of profilecomparison and pattern recognition whether one or more characteristicchemical traces do or do not occur in the tested sample. Duringdetection of the presence of a characteristic chemical compound or groupof compounds in the tested sample an auditive and/or visual signal canbe generated by a signal-generating element coupled to the processor. Itis also possible to envisage a signal being generated by thesignal-generating element after every measurement, but wherein thenature of the signal depends on the analysis results. The signal has thepurpose of alerting the lab technician to the presence or absence of oneor more characteristic traces in the tested sample. It is also possibleto envisage the measured signals being presented graphically, preferablyon a screen. Information about components present in the sample can bederived from the form of the displayed signals.

The support structure is preferably configured to substantially whollyenclose at least the container of the at least one assembly. The supportstructure is provided here with one or more receiving spaces for theassembly. It is possible to envisage a single receiving space beingsuitable for accommodating multiple assemblies simultaneously. Throughthe use of one or more receiving spaces the support structure in factforms a housing for the assemblies, wherein at least the containers ofthe assemblies are at least partially enclosed. The support structure ispreferably manufactured here from a material which blocks ultravioletambient radiation so that degradation of the biological sample can beprevented. The top structure is preferably embodied as a cover so as toenable the at least one assembly to be wholly enclosed by the device.The top structure will usually be pivotally connected here to thesupport structure. It is however also possible to envisage the topstructure being releasably connected to the support structure so thatthe top structure can be completely removed when at least one assemblyis placed in or on the support structure. Following placing of the atleast one assembly, the top structure can be attached to the supportstructure and preferably be locked relative to the support structure.The above described support structure and components thereof can bedeemed as a unit. It is also possible to envisage coupling a number ofunits to each other in optionally releasable manner, whereby a modularsystem is generated. It is in this way possible to analyse a largernumber of samples at the same time with one system.

The top structure, particularly the at least one sealing element, ispreferably configured to engage substantially medium-tightly on aclosing body of the closing element around an analysis opening arrangedin the closing body. After opening of the ventilating channel, theanalysis opening is connected to the ventilating channel, whereby themetabolic gas for analysis can be guided relatively quickly andefficiently into the analysis device, wherein the risk of metabolic gasescaping is minimized.

In a preferred embodiment the device comprises at least one heatingelement for heating the biological sample received in at least onecontainer. Heating the biological sample to a typical temperature ofabout 37° C. has the advantage that the metabolic activity and thereplication speed of micro-organisms (bacteria) present in thebiological sample is increased considerably, whereby the final analysistime can be considerably reduced. At this increased temperature theanalysis time is generally between 4 hours and 5 days, depending on thetype of bacterium. Positioning the heating element in the top structurehas a two-fold advantage. A significant advantage is that the heat is inthis way generated at a distance from the sample, whereby the sampletemperature can be regulated relatively well and overheating of thesample can be prevented. For the purpose of distributing the generatedheat inside the device in the direction of the container and the samplereceived therein it is advantageous for the device to comprise at leastone fan.

In an advantageous embodiment variant the sample is kept in motion inthe device. This movement can be continuous or discontinuous. Themovement is preferably realized by vibrating, moving or shaking theassembly or via a magnetic element which is added to the container orarranged in the sample and is kept in motion via an external magnet. Thesupport structure can comprise at least one turbulence-generatingelement here for causing shaking and/or vibration of the at least oneassembly. Keeping the sample in motion can considerably increase themetabolic activity and the replication speed of the bacteria in thesample, which can considerably enhance the final qualitative analysis.

In a preferred embodiment the device comprises at least onepreconcentrator for temporarily binding by means of adsorption one ormore gas components coming from the sample. The preconcentrator willgenerally be arranged here in the analysis compartment. Once theanalysis compartment has been exposed for a sufficient length of time toa gas mixture from the sample, the gas components present on or in thepreconcentrator are released therefrom by means of heating and,preferably via a pump system, guided along the at least one chemicaltrace detector. The preconcentrator can be cleaned after use by removingcomponents which may still be bound thereto. Use is preferably made hereof the circulating system which draws in and guides optionally purifiedambient air through or along the preconcentrator. The preconcentratorcan optionally be heated here to enable improved cleaning.

The device preferably takes a mobile, in particular portable, form,whereby it is relatively easy to displace the device to a suitablelocation or destination. The mobile character of the device canconsiderably increase the applicability of the device. When the devicecomprises at least one electrical energy source which is at leastcoupled to the at least one chemical trace detector, the device canfunction fully autonomously, which is particularly advantageous. Thiscan provide further advantage particularly in less developed countriesbecause a mains supply is not usually available, or available to alimited extent.

The invention also relates to a method for analysing biological samplesby making use of an assembly according to the invention, andparticularly by also making use of the device according to theinvention, comprising of: A) providing an assembly of a container and aclosing element connected to the container, B) injecting a biologicalsample via the at least one penetrable element of the closing elementinto the container, C) having the at least one ventilating channel ofthe closing element connect in substantially medium-tight manner to atleast an analysis compartment provided with at least one chemical tracedetector, D) allowing metabolic gas formed in the container to displacevia the ventilating channel and the bacterial filter of the closingelement into the analysis compartment, and E) at least partiallyanalysing the metabolic gas in the analysis compartment with at leastone chemical trace detector. In order to shorten the analysis time it isadvantageous for the method to comprise step F), comprising of heatingand/or keeping in motion for a period of time the biological sampleinjected into the container. Further advantages and embodiment variantshave already been described at length in the foregoing.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be elucidated on the basis of the non-limitativeexemplary embodiments shown in the following figures. Herein:

FIG. 1 is a perspective bottom view of a closing element according tothe invention,

FIG. 2 is a perspective view of an assembly of a container for abiological sample and the closing element according to FIG. 1 connectedto the container,

FIG. 3 shows a cross-section of an upper part of the assembly accordingto FIG. 2,

FIG. 4 shows another cross-section of an upper part of the assemblyaccording to FIGS. 2 and 3,

FIG. 5 shows a schematic cross-section of a device for analysingbiological samples in which multiple assemblies according to FIGS. 2-4are received,

FIG. 6 is a perspective, cut-away view of the device according to FIG.5, and

FIG. 7 is a schematic view of a chemical trace detector for use in thedevice according to FIGS. 5 and 6.

DESCRIPTION OF THE INVENTION

FIG. 1 is a perspective bottom view of a closing element 1 according tothe invention. Closing element 1 is configured to be arranged on acontainer 2 for holding a biological (human or animal or vegetable)sample (see FIG. 2), wherein container 2 is partially enclosed byclosing element 1. Closing element 1 here comprises a cap-like closingbody 3 provided with a central (analysis) opening 4 which in practicewill not be visible in the view according to FIG. 1 but is neverthelessdrawn for the sake of completeness. Closing body 3 will generally bemanufactured from plastic or metal. Central opening 4 is closed by aseptum 5 which is manufactured from an elastomer and enclosed by closingbody 3. Septum 5 is provided with a ventilating channel 6 provided witha membrane 7. Membrane 7 functions as bacterial filter, wherein bacteriacannot pass through membrane 7, while gas can pass through membrane 7relatively unhindered. On a peripheral side the membrane 7 connectsclosely to an inner wall of ventilating channel 6 so that gas can onlypass through ventilating channel 6 via membrane 7. A lower outer end ofventilating channel 6 is clear and in assembled state (see FIG. 2) is inopen contact with an atmosphere enclosed by container 2. In unloadedstate (rest position) an upper outer end of ventilating channel 6connects to closing body 3. The upper outer end of ventilating channel 6can be opened by exerting an (axial) pressure on septum 5 in a directionaway from closing body 3 (see FIG. 4), after which gas present incontainer 2 can leave the container substantially unhindered viaventilating channel 6. Displacement of gas from container 2 viaventilating channel 6 to an area outside container 2 generally takesplace relatively quickly as a result of diffusion. The gas displacementcan be reinforced by heating gas present in container 2, whereby aconvection flow will be set into motion, or by applying a pressuredifference over membrane 7 by means of an additional pump, wherein anunderpressure is applied outside the assembly of closing element 1 andcontainer 2 whereby accelerated diffusion is forced. Container 2 isformed in this exemplary embodiment by a plastic or glass sample bottlewith a typical volume of between 20 and 100 milliliters. Container 2 isparticularly configured to hold a biological sample of a human, ananimal or a plant. Metabolism will occur in or on the sample due tomicrobiological activity in the sample, which results in metabolic gasformation. The composition of this metabolic gas formation can becharacteristic for the presence of a disease from which the person oranimal in question is suffering, or for a bacterium, parasite or fungus.Applying the particular closing element 1 can allow the gases formed incontainer 2 to leave the assembly of closing element 1 and container 2in relatively simple manner so that the composition of said gases can bedetermined by means of an electronic nose, in particular a chemicaltrace detector comprising one or more metal oxide sensors(semi-conducting sensors), without having to penetrate the assembly ofcontainer 2 and closing element 1, for instance by means of an analysisneedle. This is particularly advantageous from a hygiene and safetyviewpoint.

FIG. 3 shows that closing body 3 connects closely to a neck 8 ofcontainer 2. Also shown is that septum 5 is clamped between closing body3 and an upper side of neck 8 of container 2. The eccentricallypositioned ventilating channel 6 has a variable diameter, wherein theupper outer end 6 a of ventilating channel 6 is wider than the lowerouter end 6 b of ventilating channel 6. Septum 5 has an internaldiameter substantially identical to an external diameter of the upperouter end 6 a of ventilating channel 6, whereby septum 5 fits closelyonto an inner wall of the upper outer end 6 a of ventilating channel 6and wherein septum 5 is supported by the narrower lower outer end 6 b ofventilating channel 6. Further shown clearly in FIG. 3 is that upperouter end 6 b of ventilating channel 6 connects in the shown unloadedstate to an inner side of closing body 3. Shown in more detail in thecross-section according to FIG. 4 is that in unloaded state aroundcentral opening 4 the septum 5 connects substantially gas-tightly to aninner side of closing body 3. A central part of septum 5 lying in linewith central opening 4 of closing body 3 is provided with an uprightbush 9 provided with a plurality of passage slots 10, whereby acrenellated structure is obtained. An analysis device 11 for analysingmetabolic gases formed in the sample received in container 2 willgenerally engage medium-tightly on an upper side of closing body 3 byapplying a sealing element 12. Sealing element 12 here encloses ananalysis compartment 13, a lower outer end of which is configured forco-action with the upright bush 9 of septum 5 such that analysiscompartment 13 presses the bush in downward direction to some extent (inthe direction of container 2), whereby the seal between septum 5 andclosing body 3 is released, after which gas formed in container 5 candisplace substantially freely via ventilating channel 6 (not shown inFIG. 4) and via passage slots 10 into analysis compartment 13, where theactual analysis of the composition of the received gases can beperformed.

FIG. 5 shows a schematic cross-section hereof and FIG. 6 shows atransparent perspective view of a portable device 11 for analysingbiological sample in which multiple assemblies according to FIGS. 2-4are received. Device 11 comprises a support structure 14 configured ashousing for four assemblies of a container 2 provided with biologicalsample and a closing element 1 mounted thereon. Support structure 14comprises for this purpose four receiving spaces 15 which aresufficiently large to accommodate the assemblies 2. Device 11 furthercomprises a top structure 17 pivotally connected to support structure 14by means of a hinge 16. Top structure 17 functions here as cover, usingwhich the receiving spaces 15 can be substantially fully closed. Topstructure 17 can optionally be coupled releasably to support structure14. It is possible here to envisage connecting top structure 17 tosupport structure 14 in other manner, for instance by means of a bayonetclosure, so that top structure 17 can engage under bias on supportstructure 14, and thereby on assemblies 2, which generally enhances thesealing capacity of device 11. Top structure 17 comprises a plurality ofanalysis compartments 13, wherein each analysis compartment 13 isconfigured to connect to an upper side of a closing element of anassembly. Each analysis compartment 13 is surrounded here by a sealingelement 12 for the purpose of realizing a medium-tight closure betweentop structure 17 and each closing element 1. A chemical trace detector18 is positioned in each analysis compartment 13 for the purpose ofanalysing metabolic gases vented from container 2 via closing element 1.Device 11 further comprises a heating element 19 and a fan 20 forrespectively heating and spreading heat in the receiving spaces so thatthe biological samples are heated to a temperature of preferably between35 and 40 degrees Celsius. In this exemplary embodiment a shaker plate21 is provided at the bottom of each receiving space 15 of supportstructure 14 for the purpose of keeping the biological samples inmotion, this usually enhancing the microbiological activity. Device 11can optionally be shaken by external shaking equipment. A battery 22incorporated into top structure 17 ensures that sufficient electricalenergy is supplied for performing the measurements and optionallycontrolling heating element 19. Alternatively, device 11 can also beconnected to the mains supply. A central processor 23 provides forcontrol of the electrical components of device 11. Device 11 is providedwith a handle 24 in order to facilitate carrying of device 11. Topstructure 17 is preferably pivotable relative to support structure 14between an opened position, in which the assemblies can be placed in orremoved from support structure 14 in relatively simple manner, and a(shown) closed position in which the assemblies are enclosed by device11 in substantially medium-tight (gas and liquid-tight) manner. In theshown situation it can be advantageous to lock top structure 17 relativeto support structure 14 by means of a locking element 25. Multiplesamples present in the plurality of assemblies 2 can be analysedsimultaneously by means of device 11.

FIG. 7 is a schematic view of a chemical trace detector 31 for use inthe device according to FIGS. 5 and 6. Detector 31 comprises here aheatable semi-conducting sensor 32, also referred to as hotplate sensor.Semi-conducting sensor 32 preferably comprises a (semi-conducting) metaloxide layer 33 which is sensitive to chemical (redox) reactions takingplace in the immediate vicinity, and a heating element 34 for heatingthe metal oxide layer 33. The metal oxide layer 33 exhibits atemperature-dependent change in resistance subject to chemical traceswhich react on or close to a free surface 35 of the metal oxide layer33. Heating element 34 is preferably mounted on or close to the metaloxide layer 33 and is preferably manufactured by means ofMicro-Electrical Mechanical Systems (MEMS) technology, so that thetemperature of the metal oxide layer 33 will be substantially identicalto the temperature of heating element 34. Heating element 34 has a lowthermal mass and is controlled by a processor 36 for the purpose ofrealizing a stable temperature in the metal oxide layer 33. This isusually achieved by applying a separate electronic circuit provided withone or more Wheatstone bridges. The metal oxide layer 33 is coupled to adetection circuit 37 for detecting the temperature-dependent resistancechange resulting from the presence of one or more chemical traces orgroups of chemical traces which react on or close to the (heated)semi-conducting sensor 32. The values measured by detection circuit 37are stored on an internal memory 38 such as a flash memory or other typeof memory. One or more detected resistance values are stored in internalmemory 38 as cross-reference to one or more predefined temperatures, sothat a footprint of the gas mixture with one or more characteristicchemical compounds 39 therein is generated which is related to the gasmixture from the sample. The information stored in memory 38 is comparedvia a communication connection 41 to a database 43 stored on a storagemedium 42 and provided with predefined footprints for known gas mixtureswith one or more characteristic chemical compounds therein. Storagemedium 42 and the associated database 43 can be wholly incorporated intothe device according to the invention, wherein communication connection41 takes place in fully wired manner. In an alternative preferredembodiment the storage medium 42 is present at a different location andcommunication connection 41 preferably takes place wirelessly. Comparingthe detected footprint to the footprint(s) stored in database 43 makesit possible to determine whether there is a ‘best match’ 44 and todetermine the presence of one or more characteristic chemical compoundsin the biological sample. The comparison and identification offootprints takes place here by means of known pattern recognition andidentification software.

It will be apparent that the invention is not limited to the exemplaryembodiments shown and described here, but that within the scope of theappended claims numerous variants are possible which will beself-evident to the skilled person in the field.

The inventive concepts described in the foregoing are illustrated on thebasis of several illustrative embodiments. It is possible to envisageindividual inventive concepts being applied without also applying otherdetails of the described embodiment. It is not necessary to elaborateexamples of all conceivable combinations of the above describedinventive concepts, since a skilled person will appreciate that multipleinventive concepts can be (re)combined so as to arrive at a specificapplication.

The invention claimed is:
 1. A system for analysing samples, comprising: at least one assembly of a container for a biological sample and a closing element connected to the container, the closing element comprising: at least one penetrable element for injecting a sample via the closing element into the container connected to the closing element, at least one ventilating channel provided with at least one bacterial filter, which bacterial filter is substantially impermeable to bacteria and is at least permeable to a metabolic gas formed in the biological sample, and a closing body enclosing the at least one penetrable element, forming a seal between the closing body and the at least one penetrable element, wherein at least one ventilating channel is closed in a substantially unloaded state by another part of the closing element and wherein opening of the ventilating channel takes place by exerting an external pressure on the closing element; and a device for analysing metabolic gas generated by biological samples by connecting to the at least one assembly of the container and the closing element, said device comprising: at least one support structure for supporting the at least one assembly of the container and the closing element; and at least one top structure connected to the support structure, wherein the top structure comprises at least one analysis compartment configured to analyse the metabolic gas, wherein the analysis compartment is configured for substantially medium-tight connection to at least one ventilating channel of the closing element of the assembly, and wherein the analysis compartment comprises at least one chemical trace detector for detecting at least one metabolic gas or composition of gases formed in the biological sample, wherein the analysis compartment mechanically presses against the at least one penetrable element of the closing element to exert the external pressure on the closing element of the assembly such that, as a direct result of the mechanical pressing action, the seal between the closing body and the at least one penetrable element is released such that the ventilating channel will be opened and displacement of the metabolic gas into the analysis compartment can take place.
 2. The system as claimed in claim 1, wherein the device is configured for simultaneous co-action with a plurality of assemblies.
 3. The system as claimed in claim 1, wherein the top structure is releasably connected to the support structure.
 4. The system as claimed in claim 1, wherein the top structure comprises at least one sealing element for realizing a substantially medium-tight seal between at least one closing element and at least one analysis compartment connecting to the at least one closing element.
 5. The system as claimed in claim 4, wherein the top structure is configured to engage substantially medium-tightly on a closing body of the closing element around an analysis opening arranged in the closing body.
 6. The system as claimed in claim 1, wherein the device comprises at least one heating element for heating the biological sample received in at least one container.
 7. The system as claimed in claim 6, wherein the device comprises at least one fan for blowing heat generated by the at least one heating element in the direction of the at least one container.
 8. The system as claimed in claim 1, wherein the device is manufactured from a thermally insulating material.
 9. The system as claimed in claim 1, wherein the device comprises at least one processor for controlling the device.
 10. The system as claimed in claim 1, wherein the device comprises a magnetic element added to the container or arranged in the sample and kept in motion by an external magnet to cause movement of the sample.
 11. The system as claimed in claim 1, wherein the device comprises at least one preconcentrator for temporarily binding at least one chemical compound coming from the sample. 